Unachukwu Uchenna, Trischler Jordis, Goldklang Monica, Xiao Rui, D'Armiento Jeanine
Center for Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Center for Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
FASEB J. 2017 Jun;31(6):2340-2351. doi: 10.1096/fj.201601063R. Epub 2017 Feb 16.
The present study tested the hypothesis that maternal smoke exposure results in fetal lung growth retardation due to dysregulation in various signaling pathways, including the Wnt (wingless-related integration site)/β-catenin pathway. Pregnant female C57BL/6J mice were exposed to cigarette smoke (100-150 mg/m) or room air, and offspring were humanely killed on 12.5, 14.5, 16.5, and 18.5 d (dpc). We assessed lung stereology with Cavalieri estimation; apoptosis with proliferating cell nuclear antigen, TUNEL, and caspase assays; and gene expression with quantitative PCR (qPCR) and RNA sequencing on lung epithelium and mesenchyme retrieved by laser capture microdissection. Results demonstrated a significant decrease in body weight and lung volume of smoke-exposed embryos. At 16.5 dpc, the reduction in lung volume was due to loss of lung mesenchymal tissue correlating with a decrease in cell proliferation ( = 10; air: 61.65% smoke: 44.21%, < 0.05). RNA sequence analysis demonstrated an alteration in the Wnt pathway, and qPCR confirmed an increased expression of secreted frizzled-related protein 1 (sFRP-1) [ = 12; relative quantification (RQ) 1 2.33, < 0.05] and down-regulation of Cyclin D1 ( = 7; RQ 1 0.61, < 0.05) in mesenchymal tissue. Furthermore, genome expression studies revealed a smoke-induced up-regulation of Rho-GTPase-dependent actin cytoskeletal signaling that can lead to loss of tissue integrity.-Unachukwu, U., Trischler, J., Goldklang, M., Xiao, R., D'Armiento, J. Maternal smoke exposure decreases mesenchymal proliferation and modulates Rho-GTPase-dependent actin cytoskeletal signaling in fetal lungs.
母亲接触香烟烟雾会导致胎儿肺生长发育迟缓，这是由于包括Wnt（无翅相关整合位点）/β-连环蛋白信号通路在内的各种信号通路失调所致。将怀孕的雌性C57BL/6J小鼠暴露于香烟烟雾（100 - 150毫克/立方米）或室内空气中，并在胚胎发育的12.5、14.5、16.5和18.5天（dpc）对后代实施安乐死。我们采用卡瓦列里估算法评估肺的立体结构；通过增殖细胞核抗原、TUNEL和半胱天冬酶检测评估细胞凋亡；并利用定量PCR（qPCR）以及对通过激光捕获显微切割获取的肺上皮和间充质进行RNA测序来检测基因表达。结果表明，暴露于烟雾中的胚胎体重和肺体积显著降低。在胚胎发育16.5天时，肺体积的减小是由于肺间充质组织减少，这与细胞增殖减少相关（n = 10；空气组：61.65%，烟雾组：44.21%，P < 0.05）。RNA序列分析显示Wnt信号通路发生改变，qPCR证实间充质组织中分泌型卷曲相关蛋白1（sFRP - 1）表达增加（n = 12；相对定量（RQ）1比2.33，P < 0.05），而细胞周期蛋白D1表达下调（n = 7；RQ 1比0.61，P < 0.05）。此外，基因组表达研究显示，烟雾会诱导Rho - GTP酶依赖性肌动蛋白细胞骨架信号上调，这可能导致组织完整性丧失。 - 乌纳丘克武，U.，特里施勒，J.，戈德克朗，M.，肖，R.，达米恩托，J. 母亲接触香烟烟雾会减少胎儿肺间充质增殖并调节Rho - GTP酶依赖性肌动蛋白细胞骨架信号。
